HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 17, 11355-11363, April 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/17/11355    most recent M707362200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schuetz, A. Articles by Arrowsmith, C. H. Search for Related Content PubMed PubMed Citation Articles by Schuetz, A. Articles by Arrowsmith, C. H. Social Bookmarking                      What's this?

Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity^*

Anja Schuetz¹, Jinrong Min^**, Abdellah Allali-Hassani, Matthieu Schapira, Michael Shuen, Peter Loppnau, Ralph Mazitschek^¶, Nick P. Kwiatkowski^¶, Timothy A. Lewis^¶, Rebecca L. Maglathin^¶, Thomas H. McLean^¶, Alexey Bochkarev^||, Alexander N. Plotnikov^**, Masoud Vedadi, and Cheryl H. Arrowsmith^||2

From the Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L5, Canada, the ^¶Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institutes of Technology, Cambridge, Massachusetts 02142, and the ^||Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology, Department of Pharmacology, and ^**Department of Physiology, University of Toronto, Toronto, Ontario M5G 1L6, Canada

Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators.

Received for publication, September 4, 2007 , and in revised form, January 22, 2008.

The atomic coordinates and structure factors (codes 3C0Y, 3C0Z, and 3C10) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by federal funds from the NCI, National Institutes of Health Initiative for Chemical Genetics under Contract N01-CO-12400. The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck, the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4 and Table 1.

¹ Present address: Protein Sample Production Facility, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.

² To whom correspondence should be addressed: 100 College St., Toronto, Ontario M5G 1L5, Canada. Tel.: 416-946-0881; Fax: 416-946-0880; E-mail: carrow{at}uhnresearch.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Bougdour, D. Maubon, P. Baldacci, P. Ortet, O. Bastien, A. Bouillon, J.-C. Barale, H. Pelloux, R. Menard, and M.-A. Hakimi Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites J. Exp. Med., April 13, 2009; 206(4): 953 - 966. [Abstract] [Full Text] [PDF]

				M. J. Bottomley, P. Lo Surdo, P. Di Giovine, A. Cirillo, R. Scarpelli, F. Ferrigno, P. Jones, P. Neddermann, R. De Francesco, C. Steinkuhler, et al. Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain J. Biol. Chem., September 26, 2008; 283(39): 26694 - 26704. [Abstract] [Full Text] [PDF]

				C. Gao, C.-C. Ho, E. Reineke, M. Lam, X. Cheng, K. J. Stanya, Y. Liu, S. Chakraborty, H.-M. Shih, and H.-Y. Kao Histone Deacetylase 7 Promotes PML Sumoylation and Is Essential for PML Nuclear Body Formation Mol. Cell. Biol., September 15, 2008; 28(18): 5658 - 5667. [Abstract] [Full Text] [PDF]